A major advance in understanding the neurobiological basis of normal and pathological behavior was the discovery that proinflammatory cytokines act in the CNS to alter behavior and induce affective and cognitive disorders. Proinflammatory cytokines can act in the neuroimmune system to alter behavior by regulating synthesis and release of several neurotransmitters. We now have data to show that TNFalpha can also act in conjunction with classical neurotransmitters to change behavior. In both cases, very little is known about endogenous protective molecules that regulate actions of proinflammatory cytokines in the brain and hence their behavioral effects. We have exciting new preliminary evidence in vivo showing that IGF-1 inhibits both sickness behavior induced by TNFalpha and spatial memory disorders that are induced by glutamate/kainate in a TNFalpha-dependent manner. We have extended these in vivo findings by showing that TNFalpha exacerbates neuronal stress only in the presence of glutamate and kainate and that IGF-I protects neurons from these insults in vitro. In Objective 1, we will further assess the possibility that IGF-I ameliorates the affective and cognitive effects of TNFalpha. Mice deficient in TNF receptors and a critical intracellular TNF receptor signaling protein known as FAN will be used. Changes in social exploration, immobility and rearing activities will used to quantify sickness behavior following i.c.v, injection of TNFalpha Objective 2 will use both TNFalpha- and TNF receptor-deficient mice to determine the in vivo contribution of TNFalpha to kainate-induced loss of spatial memory. This objective will then confirm the role of IGF-I in preventing this form of cognitive disorder. Objective 3 will explore the novel possibility that IGF-I-induced signaling proteins directly target glutamate receptors and increase expression of survival proteins to reduce excitation-induced neuronal stress. Experiments in Objective 4 will delineate the molecular signals by which TNFalpha promotes neuronal dysfunction and loss of spatial memory by using mice that lack TNF receptors or FAN and determining if TNFalpha increases glutamate receptor activation. This objective will also determine how IGF-I counterbalances TNFalpha-induced neuronal stress. These studies are needed to learn how TNFalpha interacts with an endogenous protective factor in the brain. These innovative experiments will advance our understanding of brain and immune communication systems that control the neurobiological basis of behavioral disorders